The present invention relates to novel bis[bis(diphenylphosphino)hydrocarbon]- and bis[diphenylphosphinodiphenylarsino)hydrocarbon]-group VIII metal compounds, which have tumor cell growth-inhibiting activity, novel pharmaceutical compositions containing tumor cell growth-inhibiting amounts of such compounds and a method for treating tumor cells sensitive to such compounds by administering tumor cell growth-inhibiting amounts of such compounds to a host animal afflicted by such tumor cells.
Group VIII-transition metal complexes, especially diamminoplatinum dichloride and its use for the treatment of several types of cancer, for example testis and ovarium carcinomes, have been described by:
M. J. Cleare and P. C. Hydes, Metal Ions in Biological Systems, Vol. 11.
H. Sigel Edit., Marcel Dekker, New York (1980), 1-62 and
S. Haghighi and C. A. McAuliffe, Rev. Inorg. Chem., 3, 291-351 (1981).
Further research have been made to cis-diammino-platinum dichloride related metal-amine complexes. Said compounds do not show activity in several antitumor test systems in mice or show a diminished activity with respect to active platinum compounds.
Metal complexes of non-nitrogeneous ligand systems have scarely been studied and, except for the phosphino-hydrocarbon-group IB-metal complexes that will be mentioned later, none of these exhibit a remarkable antitumor activity [S. Haghighi and C. A. McAuliffe, Rev. Inorg. Chem., 3, 219-351 (1981)].
There still exists a strong need for new chemotherapeutica for the treatment of cancer.
This type of chemotherapeutica should show a higher activity against certain tumors or an activity against a broader spectrum of tumors. It is of further importance that such a compound is capable of overcoming the resistance to existing antitumor chemotherapeutica.
Now, pharmaceutical active compounds of the formula 1 have been found, wherein:
D.sub.1 =D.sub.2 =phosphorus or D.sub.1 =phosphorus and D.sub.2 =arsenic;
A=(CH.sub.2).sub.2, (CH.sub.2).sub.3 or cis-CH=CH;
X.sub.1 =X.sub.2 (both if present)=halo or nitrato or X.sub.1 +X.sub.2 =peroxo;
Y (if present)=halide, nitrate, perchlorate, triflate or tetrahaloferrate (III);
n=0, 1 or 2;
M= Fe(II), Fe(III), Co(II), Rh(I), Rh(III), Ir(I), Ir(III), Ni(II) or Pd(II).
Such nitrogen free metal complexes exhibit an important antitumor activity. They show surprising good results against P388 lymphocytic leukemia and B16 melanoma. Especially the high activity against B16 melanoma is remarkable.
The activity found is particularly unexpected, since most of the compounds are cationogenic and the corresponding cationogenic amino-platinum complexes are known to show no antitumor activity.
In this context reference is made to Nelson et al., J. Chem. Soc., Dalton Trans., 1778 (1975), disclosing bis[cis-1,2-bis-(diphenylphosphino)ethylene] dichloro iron(II) and bis[cis-1,2-bis -(diphenylphoshino)ethylene] dichloro iron(III) tetrachloroferrate(III). Sacconi et al., Inorg. Chem., 20, 3423 (1981), disclose the X-ray crystal structure of the above mentioned iron(II) complex. Chatt et al., J. Chem. Soc., 5504 (1961), disclose bis[1,2-bis-(diphenyl phosphino)ethane] bromo cobalt(II) bromide. Sacco et al. Gazz. Chim. Ital., 93, 687 (1963), disclose several bis [1,2-bis-(diphenyl phosphino) ethane] cobalt(II) complexes (among others, bromide, iodide, perchlorate, nitrate) and bis[1,2-bis(diphenylphosphino)ethane] nickel(II) diperchlorate. Schmid et al., Z. Naturforsch. 20b, 1008 (1965), disclose bis[1,2-bis(diphenylphosphino)-ethane] chloro cobalt(II) chloride. Sacco et al., J. Chem. Soc., 3274 (1964), disclose bis[1,2-bis(diphenylphosphino)ethane] rhodium(I) chloride and its perchlorate and tetraphenylborate analogs. Arnold et al., Chem. Phys. Lett., 19, 546 (1973), disclose bis[1,2-bis(diphenyl phosphino)ethane] dichloro rhodium(III) chloride. Hieber et al., Chem. Ber., 99, 2607 (1966), disclose bis[1,2-bis(diphenylphosphino) ethane] iridium(I) chloride. Sacco et al., J. Chem. Soc. Chem. Comm., 589 (1966), disclose several bis[1,2-bis(diphenylphosphino) ethane] iridium(I) complexes (chloride, bromide, iodide, perchlorate) and bis[1,2-bis(diphenylphosphino)ethane] peroxo iridium(III) perchlorate. This last compound is described in more detail by G. Rouschias et al., J. Chem. Soc., Dalton Trans., 2531 (1974). Chatt et al., J. Chem. Soc., 2537 (1962), disclose bis[1,2-bis(diphenylphosphino)ethane] nickel(II) dinitrate and bis[1,2-bis(phenylphosphino)ethane] palladium(II) dibromide. Feltham et al., J. Chem. Soc., 4587 (1964), disclose bis[1,2-bis(diphenylphosphino)ethane] palladium(II) diperchlorate. Westland, J. Chem. Soc. A., 3060 (1965), discloses several bis[1,2-bis(diphenylphosphino)ethane] palladium(II) complexes (chloride, bromide, iodide, perchlorate). Struck et al., J. Med. Chem., 9, 414 (1966) disclos cytotoxic activity for 1,2-bis-(diphenylphosphino)ethane which is used as a starting material to prepare most of the active ingredients of the pharmaceutical compositions and methods of treatment of the subject invention.
None of the aforementioned references disclose or suggest the pharmaceutical compositions or methods of treatment of the instant invention.
Hill, Johnson and Mirabelli disclose in European patent application Nr. 0 151 046 (date of filing 31.01.1985) antitumor pharmaceutical compositions and compounds for treating tumors employing [alpha-omega-bis(disubstituted phosphino)-hydrocarbon] digold(I), digold(III), disilver(I) and dicopper(I) derivatives.
Furthermore, Berners-Price, Mirabelli, Johnson and Sadler disclose in European patent application 0 164 970 (date of filing 31.05.1985) pharmaceutical compositions, containing [bis[bis(diphenylphosphino)hydrocarbon]-, [bis[bis(diethylphosphino) hydrocarbon]- and bis[(diphenylphosphino-diethylphosphino) hydrocarbon], gold(I), silver(I) or copper(I) complexes or a tris-[bis(diphenylphosphino)ethane] dicopper(I) complex.
However, there is no disclosure or suggestion in these references of group VIII metal complexes, or that they would display cytotoxic or any other pharmaceutical activity.
Not all the compounds falling within the general formula 1 are accessible. Compound [NiCl(diphos).sub.2 ]+Cl.sup.- can not be synthesized for instance [see R. Morassi and A. Dei, Inorg. Chim. Acta, 6, 314 (1972)].
It is further observed, that some combinations do not occur, due to reasons well known to the person skilled in the coordination chemistry, for instance when the metal is Pd(II) and the anion is Cl.sup.-, there is a 4-coordination and X.sub.1 and X.sub.2 do not occur. When the anion is Br.sup.-, 1X and 1Y can occur (5-coordination), when the anion is I.sup.-, 2X occur and no Y occurs (6-coordination), when the anion is ClO.sub.4.sup.-, X does not occur and there are two Y (4-coordination). However, the possibilities will be clear to anyone skilled in this field of the art.